TY - JOUR
T1 - Whole genome sequence analysis of blood lipid levels in >66,000 individuals
AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
AU - Selvaraj, Margaret Sunitha
AU - Li, Xihao
AU - Li, Zilin
AU - Pampana, Akhil
AU - Zhang, David Y.
AU - Park, Joseph
AU - Aslibekyan, Stella
AU - Bis, Joshua C.
AU - Brody, Jennifer A.
AU - Cade, Brian E.
AU - Chuang, Lee Ming
AU - Chung, Ren Hua
AU - Curran, Joanne E.
AU - de las Fuentes, Lisa
AU - de Vries, Paul S.
AU - Duggirala, Ravindranath
AU - Freedman, Barry I.
AU - Graff, Mariaelisa
AU - Guo, Xiuqing
AU - Heard-Costa, Nancy
AU - Hidalgo, Bertha
AU - Hwu, Chii Min
AU - Irvin, Marguerite R.
AU - Kelly, Tanika N.
AU - Kral, Brian G.
AU - Lange, Leslie
AU - Li, Xiaohui
AU - Lisa, Martin
AU - Lubitz, Steven A.
AU - Manichaikul, Ani W.
AU - Michael, Preuss
AU - Montasser, May E.
AU - Morrison, Alanna C.
AU - Naseri, Take
AU - Yanek, Lisa R.
AU - Mathias, RASIKA
AU - Arking, Dan
AU - Avramopoulos, Dimitrios
AU - Barron-Casella, Emily
AU - Beaty, Terri
AU - Becker, Diane M
AU - Becker, Lewis
AU - Casella, James
AU - Naik, Rakhi
AU - Post, Wendy
AU - Becker, Julia Powers
AU - Ruczinski, Ingo
AU - Salzberg, Steven
AU - Taub, Margaret
AU - Vaidya, Dhananjay
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.
AB - Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.
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U2 - 10.1038/s41467-022-33510-7
DO - 10.1038/s41467-022-33510-7
M3 - Article
C2 - 36220816
AN - SCOPUS:85139608936
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5995
ER -